1. Field of the Invention
The present invention relates to amine-borane compounds, including novel heterocyclic amine-boranes, and to a method of inhibiting enzyme (e.g., DNA topoisomerase) activity and/or combatting inflammation, hypolipidemia and/or neoplasia using amine-borane compounds.
2. Description of the Related Art
Various boron-containing compounds have previously been shown to exhibit therapeutic biological activity. For example, amineborane compounds such as amine.BH.sub.2 COOH, amine.BH.sub.2 COOMe and amine.BH.sub.2 CONHR have been demonstrated to exhibit antitumor, anti-inflammatory and hyperlipidemic activities. See, for example U.S. Pat. No. 4,312,989 issued to B. F. Spielvogel, et al, disclosing the use of amine-boranes to inhibit inflammation; see also Hall, Iris H., et al, J. Pharm. Sci., 1981, 70, 339-341.
Several of the substituted borane adducts of amines have demonstrated significant anti-tumor activity in vivo (Hall, Iris H., et al, J. Pharm. Sci., 1985, 74, 755-758; and Hall, Iris H., et al, J. Pharm. Sci., 1979, 68, 685-688). These amine compounds are, with a few exceptions, derivatives of acyclic amines.
Spielvogel et al U.S. Pat. No. 4,312,989 discloses, inter alia, amine-boranes of the formula: EQU amine.BH.sub.2 X
wherein:
X is selected from the group consisting of H,CN, and COOH; and PA1 amine is selected from the group consisting of morpholine, N-methyl morpholine, pyridine, and cyanoethyldimethylamine. PA1 R.sub.1 is selected from H, alkyl (preferably C.sub.1 -C.sub.10 linear or branched alkyl), alkylaryl, aryl, and arylalkyl; and PA1 R.sub.2 is selected from CN, COOH, COOR.sub.3, and CONHR.sub.3 where R.sub.3 is selected from H, alkyl (preferably C.sub.1 -C.sub.10 linear or branched alkyl), alkylaryl, aryl, and aralkyl. PA1 R.sub.1 is selected from H, alkyl (preferably C.sub.1 -C.sub.10 linear or branched alkyl), alkylaryl, aryl, and arylalkyl; and PA1 R.sub.2 is selected from CN, COOH, COOR.sub.3, and CONHR.sub.3 where R.sub.3 is selected from H, alkyl (preferably C.sub.1 -C.sub.10 linear or branched alkyl), alkylaryl, aryl, and aralkyl. PA1 R.sub.1 is H, alkyl (preferably C.sub.1 -C.sub.10 linear or branched alkyl), alkylaryl, aralkyl, and aryl; and PA1 R.sub.2 is selected from H, CN, COOH, COOR.sub.3 or CONHR.sub.3 where R.sub.3 is H, alkyl, alkylaryl, aralkyl, and aryl, wherein the alkyl radical or moiety preferably is C.sub.1 -C.sub.10 linear or branched alkyl.
Other literature articles relating to amine-borane compounds include: Mills, W. J. et al, "Synthesis and Characterization of Amine-Alkylcyanoboranes," Inorg. Chem., 1990, 29, 302-308; Dalacker, F., et al "Amine-Carbamoyl-.sup.10 B-borane, Darstellung Und Biologische Eigenschaften," Z. Naturforsch., 40 C., 344-350 (1985); Mills, W. J., et al, "Synthesis of Quinuclidine-Benzyl (ethylcarbamoyl)borane: The First Boron Analogue of a Phenylalanine Derivative," J. Chem. Soc., Chem. Commun., 1989, 900-902; Spielvogel, B. F., et al, "Synthesis of Some Cyano-, Amido- and Carboxyborane Adducts of Amines and Diamines," J. Inorg. Nucl. Chem., 41, 1223-1227 (1979); Mills, W. J., et al "Boron Analogues of Valine, Leucine, Isoleucine, and Phenylalanine: Syntheses of Amine-Alkyl (N-ethylcarbamoyl)boranes," Inorg. Chem., 1991, 30, 1046-1052; Weidig, C., et al, "Synthesis and Mechanism of Hydrolysis of Amine-Cyanoboranes," Inorg. Chem., 13 (7), 1763-1768 (1974); Wisian-Neilson, P., et al, "A General Synthesis of Amine-Cyanoboranes, " Inorg. Chem., 17(8) 2327-2329 (1978); Kemp, B., et al, "Synthesis and Characterization of the Cyano-and Carboxyborane Adducts of Quinuclidine," Inorg. Chem., 23, 3063-3065 (1984); Das, M. K., et al, "Synthesis and Characterization of Pseudohaloborane Adducts of Some Heteroaromatic N-Bases," Inorganic Chimica Acta, 172, 35-39 (1990); Mittakanti, M., et al, "Synthesis and Characterization of Derivatives of Pyridine-Borane Adducts," Inorg. Chem., 29, 554-556 (1990); and Martin, D. R., et al, "Reactions of Cyanotrihydroborate Ion and Its Derivatives With Halogens," J. Inorg. Nucl. Chem. 40, 9-13 (1978).
It is an object of the present invention to provide new amine-borane derivatives, including active anti-inflammatory, anti-hyperlipidemic, anti-neoplastic, and/or enzyme (e.g., DNA topoisomerase)- inhibiting agents.
Other objects and advantages will be more fully apparent from the ensuing disclosure and appended claims.